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PARP mediates binge alcohol‐induced neurodegeneration in adult rats
Author(s) -
Kouzoukas Dimitrios E.,
Schreiber Jennifer A.,
Tajuddin Nuzhath F.,
Kaja Simon,
Kim HeeYong,
Neafsey Edward J.,
Collins Michael A.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.661.7
Subject(s) - neurodegeneration , poly adp ribose polymerase , parp inhibitor , dentate gyrus , endocrinology , hippocampus , medicine , pharmacology , chemistry , biology , biochemistry , polymerase , disease , gene
Chronic alcohol (ethanol) abuse damages brain structures associated with learning and memory. This clinical neuropathological finding is corroborated by our observations of selective hippocampal (HP) and entorhinal cortical (EC) neurodegeneration in vivo in a model of repeated binge alcohol intoxication in adult rats (Majchrowicz 1975), and in vitro in repetitive binge alcohol‐treated rat adult‐age HP‐EC slice cultures (Tajuddin et al. 2014). We previously reported that 1) neurodegeneration in these two models correlated with elevated levels of a DNA repair protein, poly [ADP‐ribose] polymerase‐1 (PARP‐1), and 2) pharmacological PARP inhibition blocked the neuronal damage in the slice cultures. Despite PARP‐1's DNA repair role, its overactivation is also known to trigger parthanatos, a form of regulated neuronal necrosis. To examine the relationship in vivo between PARP activation and alcohol‐induced neuronal injury, we tested whether blocking PARP activity affects HP and EC neurodegeneration, quantified by Fluoro‐Jade B staining, in binge alcohol‐intoxicated adult male Sprague Dawley rats (above‐mentioned Majchrowicz model). Rats received alcohol (0 to 5g/kg i.g., determined by intoxication score) or dietary control every 8 hours for 4 consecutive days, with or without the PARP inhibitor, veliparib (ABT‐888; 25 mg/kg/day i.g.). Both alcohol‐treated groups had similar peak blood alcohol levels of ~360 mg/dl (~80 mM). PARP inhibition significantly suppressed the alcohol‐induced neurodegeneration in the HP dentate gyrus and the lateral EC region by 79.1% and 66.3%, respectively. These results confirm that PARP activation plays a crucial role in neurodegeneration (presumably regulated necrosis) caused by repeated severe binge alcohol intoxication. Furthermore, they provide key support for the validity of our in vitro adult‐age slice culture model of binge alcohol‐induced neuronal damage. Support or Funding Information NIH U01 AA018279 (MAC) and NIH T32 AA013527 (LUMC Alcohol Research Program)